System and method for in-vivo sampling and analysis

ABSTRACT

A system for in vivo analysis which includes agglutinative particles capable of interacting with at least one analyte so as to cause an optical change; and at least one in vivo imaging system ( 220, 230, 240 ) configured for detecting the optical change in vivo. The system may be incorporated within an ingestible capsule ( 100 ).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Application of PCT InternationalApplication No. PCT/IL03/00651, International Filing Date Aug. 7, 2003,which claims priority of US Provisional Patent Application, 60/402,703,filed Aug. 13, 2002, both of which being incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

The present invention relates to the field of in vivo diagnostics. Morespecifically, the present invention relates to a system and method forin vivo and in-situ sampling and analysis of conditions prevailing in abody lumen.

BACKGROUND OF THE INVENTION

An atypical concentration or presence of substances in body fluids or inbody lumens may be indicative of the biological condition of the body.For example, the presence of elevated concentrations of red blood cellsin the gastrointestinal (GI) tract may indicate different pathologies,depending on the location of the bleeding along the GI tract. Likewise,abnormalities in the physical conditions of the body, such as elevatedtemperature, may indicate pathology. Early detection, identification andlocation of abnormal conditions may be critical for correctly diagnosingand treating various pathologies.

Medical detection kits are usually based on in vitro testing of bodyfluid samples for the presence of a suspected substance. A known invitro test is, for example, an agglutination test. Agglutination teststypically rely on the ability of an antibody to form large cross-linkedantibody-antigen complexes that precipitate out of a solution. Theprocess of agglutination normally includes 2 steps: sensitization(involves the attachment of antibodies (Ab) to antigens (Ag)) andlattice formation (cross lining between sensitized particles, whichresults in visual agglutination). Some factors can enhance thesereactions, for example, pH, temperature, incubation time, ionic strength(salt concentration) of the suspending solution and so on.

Agglutination reactions, also referred to as the indirect Coombs test,usually involve the precipitation of cells. Frequently, indirectcross-linking is used to form the aggregation. A secondary antibody maybe added that binds to the primary antibodies that have bound to theirepitope on the surface of the cell. Another known group of agglutinationtests are the Latex Agglutination Tests (LAT). These immunoassay testshave been in clinical use for more than 50 years. The tests are used todetect the presence of an antibody or antigen in a variety of in vitrosamples of bodily fluids including saliva, urine, cerebrospinal fluid,gastrointestinal secretions or blood. Depending on the sample underinvestigation, and the specific substance one is looking for, eitherantibodies or antigens are attached to latex beads (typically, sphericalbeads). When the corresponding antigen or antibody is present, the latexbeads agglutinate, i.e. clump together into visible particles, whenmixed or come to contact with the sample. The latex beads may bereplaced by other polymers such as polystyrene or even gold particles.

Agglutination tests are typically performed on glass slides, “cards”with depressions for adding Ag and Ab or tubes and strips on which theagglutination exposes the underlying colored markers.

In vitro testing of samples does not easily enable the localization oridentification of the origin of an abnormally occurring substance. Inmany instances localizing an abnormally occurring substance in a bodylumen greatly contributes to the identification of pathology, and theproper type of treatment and thus contributes to the facile treatment ofthe identified pathology. For example, bleeding in the stomach mayindicate an ulcer while bleeding in the small intestine may indicate thepresence of a tumor. The detection of some conditions in the GI tract,such as bleeding, is possible by endoscope. However, this possibility islimited to the upper or lower GI tract. Thus, conditions in other partsof the GI tract, such as the small intestine, are not easily detected byendoscopy.

There is therefore a need for a system and method that may enable thelocalization or identification of the origin of an abnormally occurringsubstance throughout body lumens.

SUMMARY OF THE INVENTION

There is thus provided, according to embodiments of the invention, asystem and method for in vivo and in situ sampling and analyzing.According to one embodiment a system comprises an image sensor, anillumination source and agglutinative particles. According to anotherembodiment a system comprises an image sensor, an illumination sourceand a sample chamber that contains agglutinative particles. Typically,the agglutinative particles may be capable of adhering to an analyte, ifit is present in a sample, such that clusters or precipitates ofagglutinative particles and analytes are formed. An analyte may be asubstance, such as a chemical or biological moiety, that is capable ofadhering to an agglutinative particle. According to one embodimentclusters of agglutinative particles are discernible whereasagglutinative particles that are not clustered are typicallyindiscernible.

According to an embodiment of the invention a system comprising an imagesensor, an illumination source and agglutinative particles, optionallycontained within a sample chamber, is inserted in vivo and a body lumensample, typically a fluid sample, is reacted with the agglutinativeparticles. According to one embodiment a sample is collected into thesample chamber. The sample chamber may be illuminated and imaged whilein vivo. Agglutination, should it occur in the sample, can thus beobserved in the images taken of the sample chamber, thereby providingindication of the presence of an analyte in the sample.

According to one embodiment there is provided an autonomous devicedesigned to traverse the GI tract. The device includes at least oneillumination source and at least one image sensor for obtaining imagesof the GI tract. The device, according to one embodiment, may include atransmitter for transmitting data (e.g., image data) to an externalreceiving system. According to one embodiment the device includes asample chamber, which is typically positioned in the field ofillumination and in the field of view of the image sensor. The chamber,at least portions of which may be transparent in the illuminationwavelengths, is typically open to the body lumen environment forreceiving samples from the body lumen environment. According to anotherembodiment the device comprises an optical window, typically forilluminating and imaging a body lumen through the window. Theagglutinative particles may be immobilized to a chamber on the externalsurface of the optical window (the surface facing the body lumenenvironment), such that an optical change occurring due to agglutinationmay be imaged. Thus, images of a body lumen may contain additionalinformation regarding the presence of analytes in the body lumen.Furthermore, the appearance of discernible agglutination, whichindicates the presence of an analyte, in specific images, may bedirectly associated with a specific location within the body lumen ascan be deduced from the images of the body lumen or by otherlocalization methods.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be understood and appreciated more fully fromthe following detailed description taken in conjunction with theappended drawings in which:

FIG. 1 is a schematic illustration of a system according to oneembodiment of the invention;

FIG. 2A is a schematic illustration of agglutinative particles inaccordance with an embodiment of the invention;

FIGS. 2B-E schematically illustrate a chamber including agglutinativeparticles in accordance with embodiments of the invention;

FIG. 3 is a schematic illustration of an in vivo imaging deviceaccording to an embodiment of the invention; and

FIG. 4 is a box diagram illustrating a method for in vivo sampling andanalyzing, according to an embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, various aspects of the present inventionwill be described. For purposes of explanation, specific configurationsand details are set forth in order to provide a thorough understandingof the present invention. However, it will also be apparent to oneskilled in the art that the present invention may be practiced withoutthe specific details presented herein. Furthermore, well-known featuresmay be omitted or simplified in order not to obscure the presentinvention.

A system, according to embodiments of the invention, is typicallydesigned to be inserted in and/or passed through a body lumen forsampling contents of the body lumen. A sample or samples may becollected into one or more sample chamber(s). The sample chamber, whichtypically contains agglutinative particles, may be illuminated andimaged while it is in a body lumen such that optically discernableindication of the presence of a specific analyte may show up in theimages.

An exemplary system, according to one embodiment of the invention, isillustrated in FIG. 1. The system 20 comprises a sample chamber 22, andan optical detecting unit, e.g., imaging system 30. Imaging system 30comprises an illumination source 32 and an image sensor 34. Theillumination source 32 may illuminate chamber 22 and may also illuminatea body lumen. The image sensor 34 may image chamber 22 and may alsoimage the body lumen. The imaging system 30 may further comprise anoptical system (not shown), which may include, for example, lensesand/or collimators for collecting reflected light and for focusing animage on the image sensor 34. According to other embodiments the system20 may include a plurality of illumination sources and/or a plurality ofimage sensors. Image sensor 34 may be any sensor suitable for in vivoimaging, for example an imager, such as a CCD, CMOS imaging chip,photodiodes etc. The image sensor 34 may process the received light raysfor example by forming an image of the chamber. The image may be storedin the imaging system 30 or may be further transmitted to an externalreceiving system. In alternate embodiments other optical detectors maybe used for detecting agglutination in the chamber 22. Typically,agglutination may cause a change in the optical characteristics of asample. For example, agglutination may cause a change of color, a changein the optical density, in scattering, transparency, and so on. A devicesuitable for receiving and processing light rays that have passedthrough chamber 22, such as a spectrophotometer, may be used, forexample, to detect optical characteristics of a sample in the samplechamber 22.

Sample chamber 22, according to some embodiments, comprises a chambercavity enclosed by two sides 25, a bottom 26 and a membrane 24, themembrane 24 typically constituting a partition between the body lumenenvironment and the chamber cavity. According to some embodiments atleast the bottom 26 of the chamber 22 may be transparent in thewavelength of illumination. According to other embodiments one or two ofthe sides 25 are transparent in the illumination wavelength. Accordingto yet other embodiments any of bottom 26 or sides 25 may comprise areflecting surface, for example, for more effectively collectingreflected light. In this case, light rays traversing the chamber will beessentially all reflected back to the image sensor. In alternateembodiments chamber 22 may comprise other components and have othershapes, such as a sack-like, rectangular or cylindrical shape.

Chamber 22, which is typically configured for containing endo-luminalsamples, such as body lumen fluids, may contain agglutinative particles,such that agglutination may occur in the sample chamber if the samplecontains specific analytes (for example, as further detailed below).

When the system 20 is introduced into a body lumen the lumen environmentis sampled. An endo-luminal sample may passively enter the chamber 22through membrane 24. Alternatively, the sample may be actively drawninto the chamber, for example, based on osmotic pump technology, whereinflux of fluids into the chamber is typically a function of pore size andthe outside to inside concentration gradient. Alternatively, thesampling can be periodic, controlled, for example, by a switch.

Membrane 24 of chamber 22 may be fabricated from any suitable material,for example from silicon materials, polysulphone, and more. According toone embodiment the membrane may have properties, such ashydrophilicity/hydrophobicity or the membrane may be charged to attractor repel certain analytes. According to another embodiment the membrane24 is a semi-permeable membrane. According to one embodiment themembrane is permeable to relatively large molecules such as antibodycomplexes. According to other embodiments the membrane 24 may have anydesired cut off size. For example, the cut off size may be compatiblewith the size of a suspected analyte or substance. Typically, membrane24 may include a mesh having a pore size larger than the size of asuspected substance so as to enable the passing of the substance throughthe membrane into the chamber cavity. According to other embodiments thecut off size may be designed to retain the agglutinative particleswithin the chamber cavity. In alternate embodiments agglutinativeparticles may be immobilized in the chamber 22, such as by beingimmobilized to a chamber side or bottom or to an appendage that isrestricted to the chamber. It should be appreciated by a person skilledin the art that the agglutinative particles, according to embodiments ofthe invention, require a certain amount of mobility in order toagglutinate. For example, agglutinative particles may be embedded in agel that coats the inside of the chamber wall or bottom. In alternativeembodiments the agglutinative particles may be held against a chamberside by electric charge attraction, or magnetic forces.

Imaging system 30 transmits and receives light to and from chamber 22.Chamber 22 may be illuminated by illumination source 32 such thatoptical changes, typically as a result of the interaction betweenagglutinative particles and analytes, which may occur in the chamber 22,may be detected by image sensor 34.

An optical change may include any change, typically in an in vivosample, that may be detected by an optical detector, such as an imagesensor. Examples of possible optical changes may include a change incolor, hue, brightness, intensity, optical density, transparency, lightscattering etc., or a combination of optical changes.

It will be appreciated that chamber 22 may be made of any suitablematerial such as plastic, glass etc. Parameters to be considered whileassessing if a material is suitable may be, for example, the material'stransparency, its safety for internal use, its durability underendo-luminal conditions and so on.

The system 20 may comprise one or more chambers such that the presenceand/or concentration of one or more substances may be detectedsimultaneously or at different areas of the lumen.

The reaction between an agglutinative particle and an analyte may bereversible in which case the agglutinative particles may be used todetect a plurality of analyte sources, each source showing as a singleevent of an optical change. Also, the reaction kinetics may be such thatthe extent of the agglutination (which can be directly proportional tothe intensity of the optical change) is proportional to the analyteconcentration. According to certain embodiments a system may becalibrated for different agglutinative particles and analytes such thatthe concentration of an analyte in a sample may be deduced, as known inthe art. For example, concentrations of analytes in agglutinationreactions may be tested by a known system in which reactions are gradedfrom 0 to 4 as follows: 0=no agglutination; 1+=barely detectableagglutination; 2+=agglutination with 50% clearing; 3+=agglutination with75% clearing; 4+=visible cluster with suspending fluid totally cleared.In order to evaluate accurately the actual concentration of the analytein the sample, a series of dilutions is made and the “titer” isdetermined, wherein titer is the reciprocal of the highest dilutiongiving any positive reaction. Alternatively, samples may be graded by aninternal calibration system provided, for example, in one or morechambers in system 20.

The system, according to embodiments of the invention may thus enable todeduce not only the presence of a specific analyte at a specific in vivolocation, but also its concentration at that location. Alternatively,particles specific for different analytes may be mixed or placed inseparate chambers. Chamber 22 is illuminated by illumination source 32which may be any illumination source compatible with chamber 22 andimage sensor 34. Light sources such as light emitting diodes (LEDs) canbe used. Optionally, a collimator or reflector (not shown) may be usedfor collecting/directing light rays from the illumination source 32 tochamber 22 and through them to the image sensor 34.

According to one embodiment the system 20 may be set up such thatillumination source 32 and image sensor 34 are in front of chamber 22such that light transmitted from illumination source 32 transmitsthrough the transparent bottom 26 of chamber 22 and is reflected toimage sensor 34. According to one embodiment light rays (represented byarrow 11) are emitted from the illumination source 32 and are directedat the transparent bottom 26 of chamber 22. The light rays (representedby arrow 11) pass through the transparent bottom 26, and according toone embodiment, may heat the sample. Light rays (represented by arrow12) reflected from the chamber 22 are received on the image sensor 34.Alternatively, the system 20 may be set up such that chamber 22 ispositioned in between an illumination source 32 on one side and an imagesensor 34 on the other (not shown).

Differently designed components and differently set up systems may alsobe utilized according to embodiments of the invention. For example, thesystem 20 may include a chamber or plurality of chambers that do nothave a membrane but rather each chamber comprises two openings to allowcollecting and discharge and replacement of the sample in the chamber asthe system samples new areas of the body lumen environment. According tosome embodiments the chambers may be formed as capillaries etched, forexample, into a slab of glass, or formed in between two glass slabs oneof which contains preformed slots or channels.

The components of the system according to embodiments of the inventionmay be specifically designed for the system, or the system may utilizesome components from other systems that operate in body lumens, thuseconomically taking advantage of existing components. For example, thesystem of the invention may be incorporated into or affixed onto medicaldevices meant for being inserted into body lumens, such as needles,stents, endoscopes, catheters or capsules that can pass through the GItract. Endoscopes utilize a light source and sometimes an imaging devicewhile operating. Thus, the system of the invention can be incorporatedinto a suitable medical device, such as an endoscope, and utilize thedevice's light source and imaging device for detecting the presenceand/or concentration of analytes.

Reference is now made to FIG. 2A, which illustrates agglutinativeparticles according to an embodiment of the invention. Agglutinativeparticles, according to one embodiment are capable of aggregatinganalytes, typically by adhering to an analyte and/or by cross linking toother particles. Typically an agglutinative particle includes amicroscopic particle which is coated with (or otherwise adhered to)typically chemical or biological molecules such as antibodies (Ab) orantigens (Ag). According to one embodiment microscopic particles may belatex or magnetic particles. According to one embodiment agglutinativeparticles may include primary and secondary Abs such as homo-specificAbs or monoclonal Abs. Typically, antibodies may recognize andagglutinate antigenic determinants that may be present in a sample. Forexample, tumor antigens are expected to be found in a higherconcentration in the vicinity of a tumor than in remote areas or in theblood stream. Thus, antibodies that may recognize and agglutinate in thepresence of tumor antigens may additionally contribute to the diagnosisby enabling the localization of these tumor antigens, as furtherdescribed in the specification. The localization may be important for anaccurate diagnosis as most known GI tumor antigenic markers are notspecific to a single tumor type and may represent, for example gastric,pancreatic and colon tumors.

According to other embodiments agglutinative particles may includeantigenic determinants or epitopes that may be recognized by antibodiespresent in a sample. According to yet further embodiments agglutinativeparticles may include a particle having linkers attached to it, forbinding an analyte and/or for binding another particle. According toother embodiments agglutinative particles may include Ab or Ag that arechemically attached to particles, such as to latex or magneticparticles. In yet other embodiments Ab or Ag are attached to speciallyshaped particles, optionally, to enhance sensitivity of the reaction(for example, by avoiding steric hindrance of the binding process). Inother embodiments the agglutinative particles may include cells, such asbacteria (e.g., H. pylori). According to additional embodiments, anycombination of agglutinative particles may be used. Correspondingly, ananalyte may include an antigenic determinant, such as antigen bearingcells, for example, cancerous cells, viruses, bacteria, fungi and otherparasites etc. Alternatively, an analyte may be an antibody that ispresent in a body lumen, such as antibodies produced in response to aviral or bacterial attack or in response to the presence of a tumor orother pathologies. An analyte may further include substances, such aschemical or biological determinants having affinity to agglutinativeparticles.

According to one embodiment, in sample 40 an analyte 46 may bind to aparticle 42 through linkers 44 that are attached to particles 42.Linkers 44 may include, for example, Morphollno ethane sulphonic acidavailable as MES/Protein Solution (by Merk or Sigma) or WSC:1-(3-dimethylaminoprophyl)-3-ethylcarbdlimide (by Aldrich-Sigma).Particles with linkers may include, for example, OptiBind™ Polysterenemicroparticles or OptiLink™ Carboxylate-Modified Microparticles.

According to some embodiments analyte 446, which may be an antigen, mayagglutinate particles, for example, by binding to one arm 442′ of Ab 442wherein another arm 442″ of Ab 442 is bound by another analyte particle(for purposes of illustration 446′). Thus, when an analyte (such as 446and 446′) is present in a sample 40 particles, such as particles whichinclude Ab 442 will agglutinate, typically forming a visible structure.

According to some embodiments, a secondary particle 412 having arms 414may be present in the sample to ensure cross linking of Ab 442.Typically, binding of Ab 442 to an analyte may cause a change in the Ab(e.g., a chemical or a configuration change). Secondary particle 412will bind to Ab 442 only in the Ab's bound configuration (i.e., when Ab442 is bound to an analyte). Thus, agglutination of Ab 442 by secondaryparticles 412, which will occur only in the presence of an analyte(e.g., 446 and 446′), may enhance formation of visible structures.

Agglutinative particles 42, Ab 442 and/or secondary particles 412 may becolored. According to one embodiment, agglutinative particles (such asagglutinative particles 42, Ab 442 and/or secondary particles 412) mayhave different shapes and may have a diameter in the range of 0.1 to 300micron; other diameters are also possible. Typically, the agglutinativeparticles are indiscernible when they are dispersed in a sample,however, when agglutination occurs, the gathering or precipitate of theparticles becomes discernable. According to one embodiment theagglutinative particle 42 or the Ab 442 are colored such that whenagglutination occurs a color becomes visible in the sample. Typically,light absorption and scattering may be dependent on particle sizetogether with wavelength of illumination and relative viewing angle andtherefore changes in light absorption and/or scattering withagglutination, may follow generally known functions. According toanother embodiment the secondary particle 412 is colored such that whenagglutination occurs a color becomes visible in the sample. According toyet another embodiment an optically discernable reaction (such as aclouding or a color reaction) occurs once an agglutinative particlebinds, or is bound by an analyte. This optical reaction may typically bediscernable only when agglutination occurs. For example, precipitates orconglomerates may become visible when they a large enough.Alternatively, large particles may cease to scatter light effectivelyrelatively to smaller particles. It should be appreciated by a personskilled in the art that although the analyte illustrated in FIG. 2A isan antigen and the agglutinative particle illustrated in FIG. 2Aincludes an antibody, the analyte may be an antibody or any othersuitable particle or substance and the agglutinative particle mayinclude an antigen or any other suitable particle or substance.

Reference is now made to FIGS. 2B-E illustrating a sample chamberincluding agglutinative particles in which the sample does not containan analyte suitable for reacting with the agglutinative particles (e.g.,FIG. 2B) and a sample chamber including agglutinative particles in whichthe sample contains an analyte suitable for reacting with theagglutinative particles (e.g., FIG. 2C), according to embodiments of theinvention. FIGS. 2D and 2E show a chamber including agglutinativeparticles in which the sample contains an analyte suitable for reactingwith the agglutinative particles, before and after agglutination,according to embodiments of the invention. Chamber 22 may beincorporated in a device that is capable of being inserted into andpassing through body lumens, such as the GI tract, blood vessels, thereproductive tract, the urinary tract etc. For example, the chamber 22may be incorporated in a swallowbale capsule, as will be describedbelow.

According to one embodiment sample chamber 22 includes a membrane 24 anda bottom wall 26 that may be at least partially transparent. In oneembodiment the membrane 24 has a mesh size which allows an analyte 28enter the chamber but does not allow agglutinative particles 42 exit thechamber. In one embodiment the membrane cut off size is in the range of0.05 to 10 microns. Antibodies typically range in size between 100 Å to200 Å, thus they may penetrate through membrane 24 while otherparticles, such as particles 42, having a size in the range of 0.1 to300 microns are entrapped in the chamber 22. FIG. 2B illustrates asample chamber 22 containing a sample 40 that does not have an analytepresent in the sample. In this case particles 42 are randomly dispersedin sample 40 and are typically indiscernible. FIG. 2C illustrates asample chamber 22 containing a sample 40 having an analyte 28 present inthe sample. Sample 40 including the analyte 28 may flow through membrane24 into chamber 22 from a body lumen environment. The presence of ananalyte in sample 40 causes agglutination of particles 42 (such asdescribed above) and a colored (or otherwise discernible) precipitate42′ becomes discernible. Alternatively, sample 40 may become cloudy orclear or may go through any other optical change followingagglutination. As discussed above, the intensity of the optical changemay indicate the concentration of an analyte. In an alternateembodiment, for example as illustrated in FIG. 2D, membrane 24 may becolored or contain visible marks. Agglutinative particles 42 are presentin such a concentration so as to render sample 40 cloudy or otherwiseobscure when they are randomly dispersed in the sample 40 (e.g., topleft corner of FIG. 2D and in an overview, bottom left corner of FIG.2D). However, if sample 40 contains an analyte the particles 42 willagglutinate (e.g., top right corner of FIG. 2D), the cloudiness of thesample 40 will be alleviated due to the agglutination and the membrane24 may be exposed. The appearance of a visible membrane (e.g., asillustrated in the bottom left corner of FIG. 2D) 24 indicates thatthere is an analyte in the sample 40

According to another embodiment, exemplified in FIG. 2E, agglutinativeparticles 42 are immobilized within a sample chamber 22 (e.g., in twolines as illustrated in the top left corner of FIG. 2E). Beforeagglutination sample 40 may seem clear, cloudy or otherwise obscure(illustrated, for example, as an overview in the bottom left corner ofFIG. 2E). After agglutination occurs, analyte 28, which is present insample 40, agglutinates according to the immobilized agglutinativeparticles 42, e.g., in two lines (top right corner of FIG. 2E). Anoverview of the visible agglutination is illustrated in the bottom rightcorner of FIG. 2E.

Reference is now made to FIG. 3, which schematically illustrates adevice comprising a system, according to embodiments of the invention.According to one embodiment the device 100 is capable of being insertedinto and passing autonomously through body lumens, such as the GI tract.

The device 100 typically comprises a shell 101 which may include anoptical window 210. The device 100 further includes an imaging system,which comprises an illumination unit 230 and an image sensor 240.According to one embodiment the device 100 includes at least onesampling chamber 102. The sampling chamber 102′ is typically positionedin the field of illumination and in the field of view of the imagesensor 240. According to some embodiments a sampling chamber 102 may beintegrated into the device shell 101, optionally in the optical window210. According to other embodiments the device 100 does not include asample chamber, rather agglutinative particles may be embedded in amedium which may be attached onto the optical window 210, such that theagglutinative particles may be in contact with a body lumen environmentand may move through the medium to form visible formations (for examplea strip of gelatin having agglutinative particles embedded within may beattached to the optical window external surface).

The imaging system may obtain images from inside a body cavity or lumen,such as the GI tract. The imaging system also obtains images of thesampling chamber 102, such that, according to an embodiment of theinvention, a single image (frame) may contain image data of the bodylumen and image data of the agglutination.

The illumination unit 230 may include one or more discrete light sourcesor may include only one light source. The one or more light sources maybe a planar light source, a white light emitting diode (LED), or anyother suitable light source, known in the art. Optimal parameters may bechosen for a light source while taking into account, for example, thescattering of light, which is a function of the relationship between thewavelength and particle size. The device 100 includes an image sensor240, which acquires the images and an optical system 220 which focusesthe images onto the image sensor 240. The image sensor 240 may be anysuitable in vivo imager, such as a CCD or CMOS image sensor. The opticalsystem 220 may include optical elements, such as one or more lenses (notshown), one or more composite lens assemblies (not shown), one or moresuitable optical filters (not shown), or any other suitable opticalelements (not shown) adapted for focusing an image on the imagingsensor. According to one embodiment the illumination unit 230illuminates the sampling chamber 102 and inner portions of the bodylumen through the optical window 210. In an embodiment of the inventionthe device 100 may comprise a plurality of imaging devices and,optionally, their corresponding optical systems, and optionally aplurality of illumination sources. For example, a plurality of imagingdevices and optionally a plurality of interaction chambers may bepositioned at opposing sides of the device for multi-directionalsampling and/or viewing of the body lumen. Device 100 further includes atransmitter 260 and an antenna 270 for transmitting data, e.g., imagesignals of the image sensor 240, and one or more power sources 250. Thepower source(s) 250 may be any suitable power sources such as but notlimited to silver oxide batteries, lithium batteries, or otherelectrochemical cells having a high energy density, or the like. Thepower source(s) 250 may provide power to the electrical elements of thedevice 100. It is noted that for the sake of clarity of illustration,the connections between the power source 250 and the circuits orcomponents of the device 100 which receive power therefrom, are notshown in detail.

According to one embodiment, as the device 100 is transported throughthe body lumen, such as the gastrointestinal (GI) tract, the imageracquires images (frames), which are processed and transmitted to anexternal receiver/recorder (not shown) worn by the patient for recordingand storage. The recorded data may then be downloaded from thereceiver/recorder to a computer or workstation (not shown) for displayand analysis. Other systems and methods may also be suitable.

During the movement of the device 100 through the GI tract, the imagermay acquire frames at a fixed or at a variable frame acquisition rate.For example, the imager may acquire images at a fixed rate of two framesper second (2 Hz). However, other different frame rates may also beused, depending, inter alia, on the type and characteristics of thespecific imager or camera or sensor array implementation that is used,and on the available transmission bandwidth of the transmitter 260. Thedownloaded images may be displayed by the workstation by replaying themat a desired frame rate. This way, the expert or physician examining thedata is provided with a movie-like video playback, which may enable thephysician to review the passage of the device through the GI tract andto observe occurrences of agglutination.

The device 100 may be constructed as an ingestible video capsule,similarly to capsules disclosed in U.S. Pat. No. 5,604,531 to Iddan etal., WO 01/65995 to Glukhovsky et al., U.S. Pat. No. 6,240,312, toAlfano, or in WO 01/50941 to (all of which are incorporated herein byreference). A capsule optionally utilized according to anotherembodiment of the invention may be a remote-controllable, micro-scaledevice having a motion mechanism, such as a mechanical propeller thatmay be driven by an electric motor or may be turned by a build in gasflow. Another capsule may contain a rotation mechanism that can becharged by external radio waves and that can initiate capsule rotation.In alternate embodiments the system and method may be used inconjunction with other in-vivo devices, such as endoscopes, catheters,needles, stents and the like.

According to one embodiment the chamber 102 is open to the GI tractenvironment, such that GI tract fluids 370 can enter the chamber 102,typically through a membrane 102′, either passively or actively asdescribed above. The agglutinative particles (not shown) containedwithin the chamber 102 are typically restricted to the chamber. Theparticles may be unable to leave the chamber because of the membrane102′ which enables the entrance of GI tract fluids 370 but does notallow leakage of the particles from the chamber. According to oneembodiment the chamber 102 comprises sides 125 and 125′ and bottom 126.Typically, chamber 102 may be at least partially transparent to enableviewing optical changes within the chamber. According to one embodimentside 125′ is transparent so as to allow illumination from theillumination unit 230 enter the chamber for illuminating the sample.According to one embodiment side 125 and/or bottom 126 may be coated bya reflecting surface, for example, a mirror, for more effectivelycollecting reflected light and for possibly enhancing the image of thesample chamber 102. The reflective surface may have a color contrastingthat of the particles.

According to one embodiment device 100 schematically shown in FIG. 3 isdesigned to be inserted into the GI tract and pass through the entiretract. However, the device 100 is not limited to any specificconfiguration. For example, in accordance with the specific imager andspecific energy requirements, device elements (such as the illuminationsource and transmitter) may be connected by cable to an external powersupply or to an external receiving system. Alternatively, the device maybe powered externally (e.g., by an external electromagnetic field thatmay induce power in a set of coils which may be included in the device100). Further, the device may be of any shape suitable for beinginserted into a body lumen and for passing through the body lumen or forbeing included in a device that is inserted into a body lumen.

According to one embodiment, as the device 100 proceeds down the GItract, minute amounts of GI tract fluids 370 may slowly enter thechamber 102. Optionally, GI tract fluids that enter the chamber 102 inone area of the GI tract may be displaced by fluids from a newly reachedarea in the GI tract. According to some embodiments the device 100constantly samples the GI tract environment throughout the lumen. Thus,the origin or location of pathologies in the GI tract can be detected.For example, the presence of a tumor or tumor cells in a patient's GItract can be detected by inserting a device according to an embodimentof the invention into the patient's GI tract. The device may comprise asample chamber, which includes, for example, agglutinative particlesthat may specifically bind to tumor cells. For example, CAM 17.1, whichis an anti-mucin monoclonal antibody and which has recently been provenas a reagent for serological diagnosis of pancreatic cancer and has beenshown to bind to a sialic-acid-containing determinant of mucin, which isan epitope that shows wide distribution throughout the gastro-intestinaltract (Eclleston D W, Milton J D, Hoffman J, Bara J, Rhodes J M,Digestion. 1998 November-December; 59(6):665-70). Another example of asuitable agglutination assay may be the Ca 19-9 Agglutination Assay inwhich 116-NS-19-9 is monoclonal antibody generated against a coloncarcinoma cell line in order to detect a monosialoganglioside (CA19-9)found in patients with gastrointestinal adenocarcinoma.

The device 100 passively travels through the patient's GI tract imagingboth the GI tract and the sample chamber. A location of a tumor in theGI tract may be characterized by the presence of antibodies such asmentioned above. GI tract fluids sampled at the location of the tumorwill typically contain the antibodies. The antibodies react with theagglutinative particles such that agglutination occurs in the samplechamber. The agglutination, typically resulting in an optical change,may be imaged by the image sensor 240. The image of the optical changeand of the location in the GI tract may be transmitted to an externaloperator who may identify the location of the device 100 at the time theimage was produced and thus identify the origin of the tumor.

Reference is now made to FIG. 4 which is a box diagram illustrating amethod for in vivo sampling and analyzing, according to an embodiment ofthe invention. According to one embodiment a body lumen environment issampled, in vivo, in the presence of agglutinative particles (502), forexample, a sample of a body lumen may be combined with agglutinativeparticles. According to one embodiment the sample and agglutinativeparticles are combined within a chamber. The sample is observed, invivo, for optical changes (504). Typically, the step of observing thesample includes detecting at least one optical change within thecombined sample. According to one embodiment the step of detecting anoptical change is done by imaging the combined sample. Optionally,images of the sample may be transmitted to an external receiving unit.According to one embodiment the method further includes the step ofobtaining images of the body lumen.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather the scope of the present invention isdefined only by the claims, which follow:

1. An ingestible capsule comprising: an optical window, said windowhaving immobilized thereto agglutinative particles capable ofinteracting with at least one analyte and further capable of gatheringinto agglutination groups so as to cause an optical change; at least oneimaging system configured for detecting at least the optical change; anda transmitter configured for transmitting image data to an externalreceiving system.
 2. The system according to claim 1 comprising at leastone illumination source.
 3. The system according to claim 1 wherein theimaging system is configured for imaging a body lumen.
 4. The systemaccording to claim 1 wherein the agglutinative particles include atleast one molecule selected from the group consisting of: antibodies,antigens, cells and linkers.
 5. The system according to claim 1 whereinthe optical change is selected from the group consisting of: a change ofcolor, a change of hue, a change of brightness, a change of intensity, achange of optical density, a change of transparency, a change of lightscattering and any combination thereof.
 6. The system according to claim1 wherein the in vivo imaging system includes at least a photodiode, aCCD or a CMOS.
 7. The device according to claim 1 comprising at leastone chamber, said chamber configured for containing the agglutinativeparticles and an in vivo sample.
 8. The system according to claim 7wherein the chamber is at least partially transparent.
 9. The systemaccording to claim 7 wherein the imaging system is configured forimaging the chamber.
 10. The system according to claim 7 wherein the atleast one analyte is in the in vivo sample.
 11. A method for in vivoanalysis, the method comprising the steps of: obtaining a sample from abody lumen; combining in vivo the sample with agglutinative particlescapable of interacting with at least one analyte in the sample andgathering into agglutination groups; and detecting at least one opticalchange upon formation of the agglutination groups.
 12. The methodaccording to claim 11 wherein the step of detecting at least one opticalchange includes imaging the combined sample.
 13. The method according toclaim 11 comprising the step of obtaining at least one image of the bodylumen.
 14. The method according to claim 11 comprising transmitting datato an external receiving unit.
 15. The method according to claim 11further comprising the step of ingesting a capsule comprising theagglutinative particles, wherein said step of obtaining a sample isperformed using the capsule.
 16. The method according to claim 11further comprising the step of identifying a location of the combinedsample within the body lumen.
 17. The method according to claim 11,wherein the combined sample and agglutinative particles gather into theagglutinative groups proportional to the concentration of analyte in thesample.